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CS SICKNESS
643 In all probability, the patients who died clutching a nebuliser in their hands have died from having no effective anti-asthmatic medication-neither isoprenaline (to which they were tolerant) nor sufficient corticosteroids. London N.3, and Berlin 65.
H. HERXHEIMER.
*** Dr. Herxheimer’s strictures do not disturb the fact that there has been a rise and then a fall in asthma mortality associated with an increase and then a decrease in the use of pressurised aerosols. With this method of selfadministration an overdose is much more likely than with less efficient atomisers; and the unchanged mortality in the 0-4 age-group, who do not treat themselves, is compatible with the argument that excessive use of pressurised aerosols is responsible for the increase in asthma deaths. Dr. Herxheimer contrives to make our earlier leader sound like a total refutation of this argument, but readers who care to examine it will find that is very far from so.—Bn. L.
MEDICAL STAFFING IN THE N.H.S. SIR,-Dr. Bull (Sept. 6, p. 540) wants to know the justification for the facts he has worked out regarding the discrepancy in consultant staffing between England and Scotland. If he returns to his Whitaker’s Almanack he will find some more facts which are relevant. England and Wales occupy 58,338 square miles with a population of 46,000,000. Scotland has an area of over half this (29,755 square miles) for a population of 5,000,000. Only 1,830,000 of these people live in the four major cities, and the rest are scattered in the remaining 29,000 square miles. When these facts are known, I think it becomes obvious why more consultants are needed in Scotland than in England and Wales. Even with the increased number of consultants, it is still necessary for pathologists to travel from Glasgow to Oban (about 70 miles) to do necropsies. In return for this information, perhaps Dr. Bull can
enlighten me as to why English hospitals are more expensive than Scottish ones. In 1963-64, a Scottish teaching hospital cost E35 per bed per week and a London one cost E48. These are the facts-what is the justification ? RICHARD C. R. CONNOR. GlasgowW.2.
CS SICKNESS
SIR,-Your annotation (Aug. 30, p. 475) called for the publication, in a widely accessible journal, of a review of all available research
on
the riot-control agent
cs.
The
possible need for further studies might also have been suggested. Persistent sickness and diarrhoea are features of cs Radiation and radiomimetic chemicals can give rise to similar gastrointestinal disturbances.1 It would be of interest to learn whether or not evidence for chromosomal damage after cs exposure has been energetically sought. It is, perhaps, not without relevance that the potent nitrogen-mustard mutagens had their accidental origin in a war gas, and that a recent report2 put forward the possibility that chemical weapons might cause genetic
poisoning.
changes. Royal
Free Hospital School of Medicine, Hunter Street, London W.C.1.
1. 2.
L-ASPARAGINASE AND BLASTOGENESIS SIR,-Escherichia coli L-asparaginase inhibits the blastic transformation of human peripheral-blood lymphocytes stimulated by phyiohaemagglutinin (P.H.A.) in cell-culture. This happens both when the asparaginase is added directly to the culture medium and when it is given intravenously in vivo and the lymphocytes are subsequently removed and set up in the P.H.A. cell-culture.2 A possible explanation of this inhibition of blastogenesis is the depression, caused by L-asparaginase, of aminoacids necessary for cellular growth-for example, L-asparagine, L-aspartic acid, and, above all, L-glutamine. This has been suggested by numerous experiments with asparaginase in cell-culture, in experimental animals, and in humans as well. Mrs. Dartnall and Professor Baikie, however, have now pointed out that the inhibition of blastogenesis caused by L-asparaginase could also be a direct toxic effect.3 This seems to be more than a hypothesis, since Professor Baikie and his co-worker observed P.H.A. blastogenesis in culture-media without L-asparagine and L-aspartic acid. Nevertheless these aminoacids were introduced into the culture-medium by adding plasmatheir concentrations in human plasma, are, in fact, 0-540-65 mg. per 100 ml. and 0.01-0.07 mg. per 100 ml. respectively.4 Furthermore an identical cell-culture should be made also in a medium containing no L-glutamine, since L-asparaginase causes depletion also of this aminoacid 5; and it seems that deprivation of L-glutamine is the real reason for L-asparaginase’s effect on cellular growth.6 We have now carried out further observations on the matter.
added E. coli L-asparaginase to the P.H.A. lymphocyte-cultures at different times after the culture was set up, and we were able to show that the extent of blastogenesis inhibition was the same whether the asparaginase was added at the very beginning of the culture or one hour later. When, however, asparaginase was added later still, there was a progressive increase of the blast percentages in the three-day P.H.A.-cultures, which paralleled the delay in L-asparaginase administration-in other words, it appeared that the blastic transforming process was stopped (because of a toxic or an aminoacid-depriving mechanism ?) at approximately the time when asparaginase was added to the culture. Secondly, peripheral-blood lymphocytes taken from 10 normal volunteers after intravenous injection of E. coli L-asparaginase, and set up in the three-day P.H.A.-culture, were incapable of blastogenesis. This observation agrees with that of McElwain and Hayward. The asparaginase was injected in a single dose of 200-800 i.u. per kg. Daily tests before and after administration of asparaginase have shown that the inhibition of blastogenesis lasts for several days. Is this the result of aminoacid depletion as such, or of toxicity (impurities or E. coli toxins) in the L-asparaginase preparation ? Murphy et al. reported that the halflife of L-asparaginase in a patient’s plasma after a single intravenous injection was 12-22 hours.’7 Nevertheless, we do not know how long active quantities of L-asparaginase are retained, nor whether the impurities or toxins have the same half-lives as the enzyme itself. Possibly the investigation of the P.H.A.-responsiveness of peripheral-
Firstly,
1. 2. 3. 4. 5.
W. TAMPION.
Bacq, Z. M., Alexander, P. Fundamentals of Radiobiology. Oxford, 1961. United Nations Publications A/7575/Rev. 1. New York, 1969.
6. 7.
we
Astaldi, G., Burgio, G. R., Krc, I., Genova, R., Astaldi, A. Lancet, 1969, i, 423. McElwain, T. J., Hayward, S. K. ibid. p. 527. Dartnall, J. A., Baikie, A. G. ibid. p. 1098. Stein, W. M., Moore, S. J. biol. Chem. 1954, 211, 918. Salser, J. S., Miller, H. K., Earl Balis, M. Proceedings of the Twelfth Congress of the International Society of Hæmatologists, New York, September, 1968 (abstr.). Oerkermann, H. Personal communication. Murphy, M. L., Tallal, L., Tan, E., Schwartz, M. Proceedings of the Pediatric Congress, Atlantic City, April 30-May 5, 1969.
H. HERXHEIMER.
*** Dr. Herxheimer’s strictures do not disturb the fact that there has been a rise and then a fall in asthma mortality associated with an increase and then a decrease in the use of pressurised aerosols. With this method of selfadministration an overdose is much more likely than with less efficient atomisers; and the unchanged mortality in the 0-4 age-group, who do not treat themselves, is compatible with the argument that excessive use of pressurised aerosols is responsible for the increase in asthma deaths. Dr. Herxheimer contrives to make our earlier leader sound like a total refutation of this argument, but readers who care to examine it will find that is very far from so.—Bn. L.
MEDICAL STAFFING IN THE N.H.S. SIR,-Dr. Bull (Sept. 6, p. 540) wants to know the justification for the facts he has worked out regarding the discrepancy in consultant staffing between England and Scotland. If he returns to his Whitaker’s Almanack he will find some more facts which are relevant. England and Wales occupy 58,338 square miles with a population of 46,000,000. Scotland has an area of over half this (29,755 square miles) for a population of 5,000,000. Only 1,830,000 of these people live in the four major cities, and the rest are scattered in the remaining 29,000 square miles. When these facts are known, I think it becomes obvious why more consultants are needed in Scotland than in England and Wales. Even with the increased number of consultants, it is still necessary for pathologists to travel from Glasgow to Oban (about 70 miles) to do necropsies. In return for this information, perhaps Dr. Bull can
enlighten me as to why English hospitals are more expensive than Scottish ones. In 1963-64, a Scottish teaching hospital cost E35 per bed per week and a London one cost E48. These are the facts-what is the justification ? RICHARD C. R. CONNOR. GlasgowW.2.
CS SICKNESS
SIR,-Your annotation (Aug. 30, p. 475) called for the publication, in a widely accessible journal, of a review of all available research
on
the riot-control agent
cs.
The
possible need for further studies might also have been suggested. Persistent sickness and diarrhoea are features of cs Radiation and radiomimetic chemicals can give rise to similar gastrointestinal disturbances.1 It would be of interest to learn whether or not evidence for chromosomal damage after cs exposure has been energetically sought. It is, perhaps, not without relevance that the potent nitrogen-mustard mutagens had their accidental origin in a war gas, and that a recent report2 put forward the possibility that chemical weapons might cause genetic
poisoning.
changes. Royal
Free Hospital School of Medicine, Hunter Street, London W.C.1.
1. 2.
L-ASPARAGINASE AND BLASTOGENESIS SIR,-Escherichia coli L-asparaginase inhibits the blastic transformation of human peripheral-blood lymphocytes stimulated by phyiohaemagglutinin (P.H.A.) in cell-culture. This happens both when the asparaginase is added directly to the culture medium and when it is given intravenously in vivo and the lymphocytes are subsequently removed and set up in the P.H.A. cell-culture.2 A possible explanation of this inhibition of blastogenesis is the depression, caused by L-asparaginase, of aminoacids necessary for cellular growth-for example, L-asparagine, L-aspartic acid, and, above all, L-glutamine. This has been suggested by numerous experiments with asparaginase in cell-culture, in experimental animals, and in humans as well. Mrs. Dartnall and Professor Baikie, however, have now pointed out that the inhibition of blastogenesis caused by L-asparaginase could also be a direct toxic effect.3 This seems to be more than a hypothesis, since Professor Baikie and his co-worker observed P.H.A. blastogenesis in culture-media without L-asparagine and L-aspartic acid. Nevertheless these aminoacids were introduced into the culture-medium by adding plasmatheir concentrations in human plasma, are, in fact, 0-540-65 mg. per 100 ml. and 0.01-0.07 mg. per 100 ml. respectively.4 Furthermore an identical cell-culture should be made also in a medium containing no L-glutamine, since L-asparaginase causes depletion also of this aminoacid 5; and it seems that deprivation of L-glutamine is the real reason for L-asparaginase’s effect on cellular growth.6 We have now carried out further observations on the matter.
added E. coli L-asparaginase to the P.H.A. lymphocyte-cultures at different times after the culture was set up, and we were able to show that the extent of blastogenesis inhibition was the same whether the asparaginase was added at the very beginning of the culture or one hour later. When, however, asparaginase was added later still, there was a progressive increase of the blast percentages in the three-day P.H.A.-cultures, which paralleled the delay in L-asparaginase administration-in other words, it appeared that the blastic transforming process was stopped (because of a toxic or an aminoacid-depriving mechanism ?) at approximately the time when asparaginase was added to the culture. Secondly, peripheral-blood lymphocytes taken from 10 normal volunteers after intravenous injection of E. coli L-asparaginase, and set up in the three-day P.H.A.-culture, were incapable of blastogenesis. This observation agrees with that of McElwain and Hayward. The asparaginase was injected in a single dose of 200-800 i.u. per kg. Daily tests before and after administration of asparaginase have shown that the inhibition of blastogenesis lasts for several days. Is this the result of aminoacid depletion as such, or of toxicity (impurities or E. coli toxins) in the L-asparaginase preparation ? Murphy et al. reported that the halflife of L-asparaginase in a patient’s plasma after a single intravenous injection was 12-22 hours.’7 Nevertheless, we do not know how long active quantities of L-asparaginase are retained, nor whether the impurities or toxins have the same half-lives as the enzyme itself. Possibly the investigation of the P.H.A.-responsiveness of peripheral-
Firstly,
1. 2. 3. 4. 5.
W. TAMPION.
Bacq, Z. M., Alexander, P. Fundamentals of Radiobiology. Oxford, 1961. United Nations Publications A/7575/Rev. 1. New York, 1969.
6. 7.
we
Astaldi, G., Burgio, G. R., Krc, I., Genova, R., Astaldi, A. Lancet, 1969, i, 423. McElwain, T. J., Hayward, S. K. ibid. p. 527. Dartnall, J. A., Baikie, A. G. ibid. p. 1098. Stein, W. M., Moore, S. J. biol. Chem. 1954, 211, 918. Salser, J. S., Miller, H. K., Earl Balis, M. Proceedings of the Twelfth Congress of the International Society of Hæmatologists, New York, September, 1968 (abstr.). Oerkermann, H. Personal communication. Murphy, M. L., Tallal, L., Tan, E., Schwartz, M. Proceedings of the Pediatric Congress, Atlantic City, April 30-May 5, 1969.